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Molecular and Cellular Biology

Huda H Al-Khalaf, Hazem Ghebeh, Rabia Inass, Abdelilah Aboussekhra
Aging and stress promote senescence, which has intrinsic tumor suppressor functions and extrinsic tumor promoting properties. Therefore, it is of utmost importance to delineate the effects of senescence-inducers on the various types of cells that compose the different organs. We have shown here that primary normal breast luminal (NBL) cells are more sensitive than their corresponding stromal fibroblasts to proliferative as well as oxidative damage-induced senescence. Like fibroblasts, senescent NBL cells secreted elevated amount of various cytokines including IL-6 and Il-8, expressed high level of p16, p21 and p53 while LaminB1 was down-regulated...
November 5, 2018: Molecular and Cellular Biology
James W Clancy, Christopher J Tricarico, Daniel R Marous, Crislyn D'Souza-Schorey
Tumor cell invasion is one result of the bidirectional interactions occurring between tumor cells and the surrounding milieu. The ability of tumor cells to invade through the extracellular matrix is in part regulated by the formation of a class of protease-loaded extracellular vesicles, called tumor microvesicles (TMVs), which are released directly from the cell surface. Here we show that the actin bundling protein, fascin, redistributes to the cell periphery in a ternary complex with podocalyxin and ezrin, where it promotes TMV release...
November 5, 2018: Molecular and Cellular Biology
Suneer Verma, Paul De Jesus, Sumit K Chanda, Inder M Verma
The nuclear factor-kappa B (NF-κB) family of transcription factors plays a central role in coordinating the expression of genes that control inflammation, immune responses, cell-proliferation, and a variety of other biological processes. In an attempt to identify novel regulators of this pathway, we performed whole-genome RNAi screens in physiologically relevant human macrophages in response to Lipopolysaccharides and Tumor Necrosis Factor Alpha. The top hit was SNW1, a splicing factor and transcriptional co-activator...
November 5, 2018: Molecular and Cellular Biology
Chih-Lin Hsieh
The mitochondrial (mt) genome, which consists of 16,569 base pairs of DNA with a cytosine rich light (L) strand and a heavy (H) strand, exists as a multi-copy closed circular genome within the mitochondrial matrix. The machinery for replication of the mammalian mitochondrial genome is distinct from that for replication of the nuclear genome. Three models have been proposed for mtDNA replication, and one of the key differences among them is whether extensive single-stranded regions exist on the H-strand. Here, three different methods that can detect single-stranded DNA (ssDNA) are utilized to identify the presence, location, and abundance of ssDNA on mtDNA...
November 5, 2018: Molecular and Cellular Biology
Ji Seul Han, Jung Hyun Lee, Jinuk Kong, Yul Ji, Jiwon Kim, Sung Sik Choe, Jae Bum Kim
Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in low-oxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA)-stimulated lipolysis, which is evolutionarily well conserved...
November 5, 2018: Molecular and Cellular Biology
Huda H Al-Khalaf, Bothaina Al-Harbi, Adher Al-Sayed, Maria Arafah, Asma Tulbah, Abdulaziz Jarman, Falah Al-Mohanna, Abdelilah Aboussekhra
Increasing evidence supports the critical role of active stromal adipocytes in breast cancer development and spread. However, the mediators and the mechanisms of action are still elusive. We have shown here that cancer-associated adipocytes (CAAs) isolated from 10 invasive breast carcinomas are pro-inflammatory and exhibit active phenotypes, including higher proliferative, invasive and migratory capacities as compared to their adjacent tumor-counterpart adipocytes (TCAs). Furthermore, all CAAs secreted higher level of IL-8, which is critical in mediating the paracrine pro-carcinogenic effects of these cells...
November 5, 2018: Molecular and Cellular Biology
Yu-Chang Ku, Min-Hua Lai, Chen-Chia Lo, Yi-Chuan Cheng, Jian-Tai Qiu, Woan-Yuh Tarn, Ming-Chih Lai
Recent studies have suggested that DDX3 functions in antiviral innate immunity, but the underlying mechanism remains elusive. We previously identified target mRNAs whose translation is controlled by DDX3. Pathway enrichment analysis of these targets indicated that DDX3 is involved in various infections and inflammation. Using immunoblotting, we confirmed that PACT, STAT1, GNB2, Rac1, TAK1, and p38 MAPK proteins are down-regulated by DDX3 knockdown in human monocytic THP-1 cells and epithelial HeLa cells. Polysome profiling revealed that DDX3 knockdown reduces the translational efficiency of target mRNAs...
October 29, 2018: Molecular and Cellular Biology
Takuya Tomita, Shoshiro Hirayama, Yasuyuki Sakurai, Yuki Ohte, Hidehito Yoshihara, Yasushi Saeki, Jun Hamazaki, Shigeo Murata
The proteasome is the proteolytic machinery at the center of regulated intracellular protein degradation and participates in various cellular processes. Maintaining the quality of the proteasome is therefore important for proper cell function. It is unclear, however, how proteasomes change over time and how aged proteasomes are disposed. Here, we show that the proteasome undergoes specific biochemical alterations as it ages. We generated Rpn11-Flag/EGFP tag-exchangeable knock-in mice and established a method for selective purification of old proteasomes in terms of their molecular age at the time after synthesis...
October 22, 2018: Molecular and Cellular Biology
Martina Oravcová, Mariana C Gadaleta, Minghua Nie, Michael C Reubens, Oliver Limbo, Paul Russell, Michael N Boddy
As genetic instability drives disease or loss of cell fitness, cellular safeguards have evolved to protect the genome, especially during sensitive cell cycle phases such as DNA replication. Fission yeast Brc1 has emerged as a key factor in promoting cell survival when replication forks are stalled or collapsed. Brc1 is a multi-BRCT protein that is structurally related to the budding yeast Rtt107 and human PTIP DNA damage response factors, but functional similarities appear limited. Brc1 is a dosage suppressor of a mutation in the essential Smc5-Smc6 genome stability complex, and is thought to act in a bypass pathway...
October 22, 2018: Molecular and Cellular Biology
Isabel Carrascoso, Carmen Sánchez-Jiménez, Elena Silion, José Alcalde, José M Izquierdo
Welander distal myopathy (WDM) is a muscle dystrophy characterized by adult-onset distal muscle weakness, prevalently impacting the distal long extensors of the hands and feet. WDM is an autosomal dominant disorder caused by a missense mutation (c.1362G>A; p.E384K) in the TIA1 gene, which encodes an RNA-binding protein basically required for the post-transcriptional regulation of RNAs. We have developed a heterologous cell model of WDM to study the molecular and cellular events associated with mutated TIA1 expression...
October 22, 2018: Molecular and Cellular Biology
Sachini U Siriwardena, Madusha L W Perera, Vimukthi Senevirathne, Jessica Stewart, Ashok S Bhagwat
Phorbol 12-myristate 13-acetate (PMA) promotes skin cancer in rodents. The mutations found in murine tumors are similar to those found in human skin cancers, and PMA promotes proliferation of human skin cells. PMA treatment of human keratinocytes increases the synthesis of APOBEC3A, an enzyme that converts cytosines in single-stranded DNA to uracil and mutations in a variety of human cancers are attributed to A3A or APOBEC3B expression. We tested here the possibility that induction of APOBEC3A by PMA causes genomic accumulation of uracils that may lead to such mutations...
October 22, 2018: Molecular and Cellular Biology
Himangshu S Bose, Fadi Gebrail, Brendan Marshall, Elizabeth E Perry, Randy M Whittal
Adrenal and gonadal mitochondrial metabolic activity requires electrons from cofactors, cholesterol and a substrate for rapid steroid synthesis, an essential requirement for mammalian survival. Substrate activity depends on its environment, which is regulated by chaperones and mitochondrial translocases. Cytochrome P450 side chain cleavage enzyme (Side Chain Cleavage enzyme/SCC or CYP11A1) catalyzes cholesterol to pregnenolone conversion although its mechanism of action is not well understood. We find that SCC is directly imported into the mitochondrial matrix, where its N-terminal sequence is cleaved sequentially, after which it becomes activated following the second cleavage that is dependent on the folding of the protein...
October 22, 2018: Molecular and Cellular Biology
Mischa Longyin Li, Qinqin Jiang, Natarajan V Bhanu, Junmin Wu, Weihua Li, Benjamin A Garcia, Roger A Greenberg
Proper balance between the repair of DNA double-strand breaks (DSBs) by homologous recombination and nonhomologous end-joining is critical for maintaining genome integrity and preventing tumorigenesis. This balance is regulated and fine-tuned by a variety of factors, including cell cycle and the chromatin environment. The histone acetyltransferase TIP60 was previously shown to suppress pathologic end-joining and promote homologous recombination. However, it is unknown how regulatory post-translational modifications impact TIP60 acetyltransferase activity to influence the outcome of DSB responses...
October 8, 2018: Molecular and Cellular Biology
Wei Fan, Xiu Kui Gao, Xi Sheng Rao, Yin Pu Shi, Xiao Ceng Liu, Fei Ya Wang, Yu Fen Liu, Xiao Xia Cong, Min Yi He, Shui Bo Xu, Wei Liang Shen, Yue Shen, Shi Gui Yan, Yan Luo, Boon Chuan Low, Hongwei Ouyang, Zhang Bao, Li Ling Zheng, Yi Ting Zhou
The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblast cells derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration but the precise cellular mechanism remains elusive. Here we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38MAPKα, but not AKT1, rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts...
October 1, 2018: Molecular and Cellular Biology
Jason P Tourigny, Moustafa M Saleh, Kenny Schumacher, Didier Devys, Gabriel E Zentner
Eukaryotic RNA polymerase II (RNAPII) transcribes mRNA genes and non-protein coding RNA (ncRNA) genes including those encoding small nuclear and nucleolar RNAs (sn/snoRNAs). In metazoans, RNAPII transcription of sn/snoRNAs is facilitated by a number of specialized complexes, but no such complexes have been discovered in yeast. It has been proposed that yeast sn/snoRNA and mRNA expression relies on a set of common factors, but the extent to which regulators of mRNA genes function at yeast sn/snoRNA genes is unclear...
October 1, 2018: Molecular and Cellular Biology
Victoria Rozés-Salvador, Sebastian O Siri, Melina M Musri, Cecilia Conde
The development and maintenance of multicellular organisms require specialized coordination between external cellular signals and the proteins receiving stimuli and regulating responses. A critical role in the proper functioning of these processes is played by endosomal trafficking, which enables the transport of proteins to targeted sites as well as their return to the plasma membrane through its essential components, the endosomes. During this trafficking, signaling pathways controlling functions related to the endosomal system are activated both directly and indirectly...
October 1, 2018: Molecular and Cellular Biology
Ana Andjelković, Amelia Mordas, Lyon Bruinsma, Annika Ketola, Giuseppe Cannino, Luca Giordano, Praveen K Dhandapani, Marten Szibor, Eric Dufour, Howard T Jacobs
Downregulation of Jun N-terminal kinase (JNK) signaling inhibits cell migration in diverse model systems. In Drosophila pupal development, attenuated JNK signaling in the thoracic dorsal epithelium leads to defective midline closure, resulting in cleft thorax. Here we report that concomitant expression of the Ciona intestinalis alternative oxidase, AOX, was able to compensate for JNK pathway downregulation, substantially correcting the cleft thorax phenotype. AOX expression also promoted wound-healing behavior and single cell migration in immortalized mouse embryonic fibroblasts (iMEFs), counteracting the effect of JNK pathway inhibition...
September 17, 2018: Molecular and Cellular Biology
Shota Sasaki, Mizuho Urabe, Tsukasa Maeda, Junko Suzuki, Ryota Irie, Masanori Suzuki, Yasuhiro Tomaru, Masakiyo Sakaguchi, Frank J Gonzalez, Yusuke Inoue
Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4γ was increased in liver-specific Hnf4a -null mice. The increased HNF4γ contained two variants, a known short variant, designated HNF4γ1, and a novel long variant, designated HNF4γ2. HNF4G2 mRNA was highly expressed in small intestine, and the transactivation potential of HNF4γ2 was the strongest among these variants, but the potential of HNF4γ1 was the lowest...
September 17, 2018: Molecular and Cellular Biology
Jyotsna Kumar, Neila L Kline, Daniel C Masison
Polyglutamine (polyQ) aggregates are associated with pathology in protein-folding diseases and with toxicity in the yeast Saccharomyces cerevisiae Protection from polyQ toxicity in yeast by human DnaJB6 coincides with sequestration of aggregates. Gathering of misfolded proteins into deposition sites by protein quality control (PQC) factors has led to a view that PQC processes protect cells by spatially segregating toxic aggregates. Whether DnaJB6 depends on this machinery to sequester polyQ aggregates, if this sequestration is needed for DnaJB6 to protect cells, and the identity of the deposition site are unknown...
September 17, 2018: Molecular and Cellular Biology
Ranjula Wijayatunge, Sam R Holmstrom, Samantha B Foley, Victoria E Mgbemena, Varsha Bhargava, Gerardo Lopez Perez, Kelly McCrum, Theodora S Ross
Deficiency of huntingtin interacting protein 1 (Hip1) results in degenerative phenotypes. Here we generated a Hip1 deficiency allele where a floxed transcriptional stop-cassette and a human HIP1 cDNA were knocked-in to intron 1 of mouse Hip1 locus. CMV - Cre -mediated germline excision of the stop-cassette resulted in expression of HIP1 and rescue of the Hip1 knockout phenotype. Mx1-Cre -mediated excision led to HIP1 expression in spleen, kidney and liver, and also rescued the phenotype. In contrast, hGFAP-Cre -mediated, brain-specific HIP1 expression did not rescue the phenotype...
September 17, 2018: Molecular and Cellular Biology
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